Endocrine Disruptors and Neurotoxicity: Which is the Link?
Living in an industrialized world exposes us to various manufactured products, from personal care items and consumer goods to pesticides. These everyday items may contain chemicals known as Endocrine-Disrupting Chemicals (EDCs), capable of interfering with the endocrine system's normal functioning in humans and animals.
The ubiquity of these disruptors in our surroundings means they can be inhaled or ingested, and their lipophilic nature, for the most part, allows them to accumulate in adipose tissue, potentially resulting in adverse effects immediately or later in life.
EDCs Effect on Neurological Development
The endocrine system, a complex network of glands, hormones, and receptors, regulates various physiological processes, including metabolism, growth, reproduction, and development. Many EDCs mimic estrogen, a hormone linked to the endocrine system that promotes the development of female traits in the body. Consequently, EDCs may cause diverse disorders in development that can generate later-life neurological and behavioral disorders.
Several studies have explored the impact of EDCs during neuronal development. It has been shown that early exposure to certain EDCs is linked to adverse behavioral effects in mice, such as novel recognition and short-term memory reduction, especially in males. In rats, in utero, exposure to specific EDCs has been associated with increased hyperactivity in male offspring.
This effect of EDs during the early stages of life may be linked to the brain's sensitivity to estrogens during development. Although estrogen receptors are mainly found in the reproductive system, they have also been found to play a crucial role in brain development, shaping brain synaptogenesis and neural connectivity.
Bisphenol A as a Case Study on the Need for EDCs Regulation
Bisphenol A (BPA), an EDC widely used to produce polycarbonate plastics and epoxy resins, part of water bottles, toys, sports equipment, medical devices, and coatings inside food and drink cans, has drawn significant attention lately due to the adverse effects that can produce.
Studies on mice exposed prenatally to BPA reveal sexually dimorphic behavior, anxiety, and spatial memory issues. Similar observations have been made in rats and zebrafish. Furthermore, prenatal BPA exposure has been linked to memory impairment and alterations in gene expression related to autism spectrum disorder in male mice offspring.
Regulatory authorities have already regulated its usage. The European Food Safety Authority (EFSA) first reviewed the risks associated with BPA for consumers in 2006. Recent adjustments have determined the need to decrease the tolerable daily intake from 4 micrograms to 0.2 nanograms per kilogram of body weight per day. Conversely, the Food and Drug Administration (FDA) released the first document related to BPA health effects in 2008. Since then, the FDA has been continuously pursuing studies better to understand the effects of BPA on the body.
Regulatory authorities are trying to understand and regulate the connection between EDCs and developmental neurotoxicity. The European Commission has funded the ENDpoiNTs project to understand how EDCs may cause developmental neurotoxicity and increase the risk for neuronal diseases in adult life or cause cognitive, learning, and behavioral issues. Researchers will advance scientific knowledge on the association between EDCs and developmental neurotoxicity and generate an EDC screening framework with cellular and computational tools. The project´s results will improve current policies on EDCs to protect vulnerable populations.
Zebrafish as a model for developmental neurotoxicity and endocrine-disrupting assays
Currently, a wide range of model organisms is used to study the toxicity of different molecules during development, from invertebrates like nematodes to vertebrates, including rodents. Due to their distinctive characteristics, zebrafish emerge as a highly advantageous candidate for neurotoxicity or neurodevelopmental toxicity assays.
Zebrafish develop fast, present high fecundity, and transparent embryos, facilitateg scientific research. Furthermore, their central nervous system is similar to other vertebrates, with >70% of Zebrafish genes homologous to humans. From an ethical standpoint, Zebrafish align with the 3R Principle of animal welfare (Reduction, Replacement, and Refinement of animals), making them an appealing substitute for rodents.
These unique traits collectively position Zebrafish not just as suitable but exemplary candidates for neurotoxicity, neurodevelopmental toxicity, and endocrine disruption assays.
Biobide has developed diverse assays based on Zebrafish to evaluate neurotoxicity and developmental neurotoxicity. It provides a High-Content Screening (HCS) and cost-effective methodology for assessing neurodevelopmental toxicity during the critical developmental stages. The study of potential induction of neurodevelopmental defects is designed in three phases: First, a Dose Range Finding (DRF) is set up as the concentration range for the behavior study and sets a reference point for the subsequent assessments. It is followed by the developmental neurotoxicity assay based on the light-dark transition test, where the locomotor activity is analyzed with an automated tracking system together with the morphology. Finally, HPLC-MS or another appropriate technique performs an internal dosing determination of the compound.
In parallel, Biobide has also developed several endocrine-disrupting assays in Zebrafish embryos that allow for analyzing the potential thyroid-disrupting effects by using a transgenic line with red fluorescence in the thyroid gland by image analysis. This can be complemented by measuring hormone levels by LC-Ms-Ms techniques and gene expression of the genes related to thyroid disruption or estrogen pathways.
The utilization of Zebrafish in those assays not only aligns with ethical considerations but also enhances the accuracy and relevance of the results, significantly contributing to understanding the connection between EDCs and developmental neurotoxicity.
Sources
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Bisphenol A. European Food and Safety Authority [Internet]. [updated 2023 Dec 1]; [cited 2024 Jan 29]. Available from: https://www.efsa.europa.eu/en/topics/topic/bisphenol
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